Development of a Series of Pyrrolopyridone MAT2A Inhibitors
Stephen J. Atkinson, Sharan K. Bagal, Argyrides Argyrou, Sean Askin, Tony Cheung, Elisabetta Chiarparin, Muireann Coen, Iain T. Collie, Ian L. Dale, Claudia De Fusco, Keith Dillman, Laura Evans, Lyman J. Feron, Alison J. Foster, Michael Grondine, Vasudev Kantae, Gillian M. Lamont, Scott Lamont, James T. Lynch, Sten Nilsson Lill, Graeme R. Robb, Jamal Saeh, Marianne Schimpl, James S. Scott, James M. Smith, Bharath Srinivasan, Sharon Tentarelli, Mercedes Vázquez–Chantada, David J. Wagner, Jarrod J. Walsh, David G. Watson, Beth Williamson
Abstract
The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ’9567 ( 21 ), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.